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At least 19 recordsLinked to original sources
PubMed1976

Glucocorticoid receptors: evidence for a second, non-glucocorticoid binding site.

Previous studies on cytoplasmic glucocorticoid receptors and enzyme induction led to the classification of steroids as inducers (optimal or sub-optimal), antagonists, or inactive steroids, with respect to their activity as glucocorticoids. The receptor was postulated to exist in allosteric equilibrium between two conformational states, one "active" and the other "inactive". Steroids behaved as inducers (optimal or sub-optimal), antagonists, or inactive steroids depending on their relative affinity for the active and inactive conformational state of the receptor. Another possible model would invoke multiple binding sites on a single receptor with interactions between the binding sites depending upon the particular steroid bound. To test this latter possibility, an experimental technique was developed to measure the rate of dissociation of tritiated dexamethasone ([3H]DM) or tritiated aldosterone ([3H]A) from the glucocorticoid receptor of rat liver or kidney cytosol. The dissociation of the [3H]DM-receptor at 25 C was not due to irreversible denaturation, and minimal recombination of the receptor with [3H]DM occurred. Progesterone and a number of other steroids consistently and significantly increased the dissociation rate of [3H]DM-receptor complexes in both liver and kidney cytosol. An identical effect was seen with hepatic glucocorticoid receptors labelled with [3H]A, like dexamethasone an optimal inducer. All steroids which enhanced glucocorticoid-receptor dissociation were either antagonists or sub-optimal inducers. Thus, it is postulated that glucocorticoid receptors have at least two classes of binding sites, and that occupation of the second site increases the dissociation rate of agonists from glucocorticoid receptors.

Aldosterone↗
PubMed1978

Glucocorticoid receptors and glucocorticoid-sensitive secretion of neutral proteinases in a macrophage line.

A continuous line of mouse macrophages (P388D1) has been shown to secrete elastase, collagenase, and plasminogen activator at activities comparable to those of macrophages elicited by an inflammatory stimulus in vivo. At physiologic concentrations anti-inflammatory glucocorticoids selectively and reversibly inhibited secretion of the three proteinases but did not inhibit secretion of lysozyme, a constitutive enzyme produced by the P388D1 cells. The secretion of the neutral proteinases was inhibited 50% by 2 to 10 nM dexamethasone. Proliferation of the macrophages was also glucocorticoid sensitive. The P388D1 macrophages contained about 4000 saturable glucocorticoid-binding sites per cell. Concentrations of hormone saturating the high affinity receptor site (for dexamethasone the dissociation constant for steroid-receptor binding, Kd, was 4 nM) correlated well with concentrations inhibiting secretion of the proteinases. Only glucocorticoids and progesterone competed for binding to the specific receptors. Temperature-sensitive translocation of hormone-receptor complexes from "cytoplasm" to nucleus similar to that found with rat thymocytes was demonstrated. Thus, the interaction between glucocorticoids and the P388D1 cell line provides a model for the regulation of macrophage secretion of neutral proteinases under normal and stress conditions.

Cell Line↗
PubMed1976

Reductions in glucocorticoid inhibition of glucose oxidation and presumptive glucocorticoid receptor content in rat adipocytes during aging.

Exposure of adipocytes to glucocorticoid hormones in vitro causes inhibition of glucose transport and metabolsim. Maximal inhibition of glucose oxidations is reduced from 42-50 to 22-25 to 5-8% in young, mature, and senescent rat adipocytes, respectively. Percent values also reflect absolute reductions since basal levels of glucose oxidation per cell are constant at all ages. Adipocytes of CD strain rats continue to increase in size throughout their lifespan, while cell size remains constant during the latter 80% of the Wistar adipocyte lifespan. Thus, cellular age, as well as possibly size, seems to be associated with these changes since they occur in adipocytes of both strains. Concentrations as well as absolute numbers of presumptive glucocorticoid receptors per cell are progressively reduced during maturation and aging of adipocytes in both rat strains. Glucocorticoid effects are known to require about 2 h and can be blocked by various antimetabolites during this period, reminiscent of classical steroid receptor-mediated responses. Thus, gradual loss of glucocorticoid receptors from adipocytes during maturation and aging may be related to progressively decreased glucocorticoid responsiveness.

Adipose Tissue↗
PubMed1976

Binding of cytosol receptor-glucocorticoid complexes by isolated nuclei of glucocorticoid-responsive and nonresponsive cultured cells.

Nuclear binding of the AtT-20 cytosol receptor-glucocorticoid complex was studied in a cell-free system using nuclei from steroid-responsive (AtT-20) and nonresponsive (EPO-G1) cell lines, both of which synthesize ACTH. The AtT-20 cell line was derived from a mouse pituitary adenocarcinoma, while the EPO cell line was established from a human malignant melanoma. The nonresponsive EPO cells lacked a cytosol receptor for glucocorticoids, and, when whole cells were incubated with labeled glucocorticoid, they were unable to concentrate the steroid in their nuclei. A cell-free system using AtT-20 cytosol preincubated with labeled glucocorticoid was used to study binding by isolated nuclei. Binding to isolated nuclei from both cell lines was indistinguishable, in terms of temperature sensitivity, binding capacity, and saturability. Sucrose density gradient analyses of KCl extracts of nuclei labeled under these cell-free conditions showed 3.2-3.6 S peaks. In contrast, a 4.0 S peak was observed consistently when unreacted cytosol was analyzed on high-salt gradients, suggesting that interaction with nuclei from both cell lines caused the receptor to alter its sedimentation characteristics. These findings suggest either that all cells contain nuclear acceptor sites and that target cell responsiveness is conferred solely by the presence or absence of the cytosol receptor, or that binding sites detected in isolated nuclei may be different from those observed in intact cells and may, in fact, obscure them.

Animals↗
PubMed1975

Glucocorticoid receptors in lung. Comparison between nonactivated and activated forms of the cytoplasmic glucocorticoid binding protein and their relationship to the nuclear binding protein of fetal rabbit lung.

In the absence of salt the cytoplasmic glucocorticoid receptor of fetal rabbit lung sediments at 7 S while the nuclear receptor sediments at 4 S. However, if nuclear extracts are mixed with receptor-depleted cytosol preparations in dilute buffer solutions without added salt, the nuclear 4 S receptor sediments as a 7 S species similar to that observed for the cytoplasmic form under the same conditions suggesting an interaction of the nuclear receptor with other cytosol proteins rather than with itself. In addition, both cytoplasmic and nuclear receptors sediment at 4 S in 0.4 M KCl and a major fraction of the nuclear receptor has an agarose elution profile identical to that of the cytoplasmic receptor. Thus a major fraction of the nuclear receptors is indistinguishable from the cytoplasmic receptors by the methods used. Since the cytoplasmic receptor sediments at 4 S in 0.15 M KCl, it is suggested that in vivo the glucocorticoid receptor may exist as a 4 S species and that the 7 S form described previously may result from an interaction of the 4 S component with other cytosol proteins in hypotonic media. About 25% of the receptor present in nuclear extracts has an agarose elution profile different from that of the cytoplasmic receptor in 0.4 M KCl. This suggests that either the nuclear receptor associates with itself or other nuclear proteins or that more than one form of nuclear receptor exists. Earlier observations suggested that in the absence of hormone the glucocorticoid receptor is localized exclusively in the cytoplasm of lung cells and that the nuclear receptor is formed by a transfer of the cytoplasmic steroid-receptor complex into the nucleus. A prerequisite for this transfer seems to be a modification of the receptor to an active form which can bind to nuclei. This receptor transfomration, referred to in this paper as activation of the receptor, can occur in the absence of nuclei and is highly dependent on temperature and ionic strength. Cytoplasmic receptors activated either by heating or by exposure to high ionic strength are indistinguishable from nonactivated receptors by sucrose density gradient analysis or by agarose gel filtration in solutions containing 0.4 M KCl. Simiarly, no significant difference in the absence of salt is observed after activation by heating. These results suggest that activation of the cytoplasmic glucocorticoid receptor involves conformational changes which favor its transfer and/or binding to nuclear sites rather than conversion of a 4 S species to a faster-sedimenting form by dimerization or by addition of another protein unit as has been proposed for the activation of the estrogen receptor of the rat uterus.

Animals↗
PubMed1975

Serum-free growth of HTC cells containing glucocorticoid- and insulin-inducible tyrosine aminotransferase and cytoplasmic glucocorticoid receptors.

HTC cells have been made to grow in chemically defined medium without any macromolecular supplements whatsoever. Initial estimates of their relative amino acid requirements have been made. The cells grown in the defined medium retain many of the differentiated features which have been the focus of investigation in their serum-grown counterparts. Thus, the cells in defined medium contain cytoplasmic glucocorticoid receptors and have tyrosine aminotransferase which can be induced by glucocorticoids, serum or insulin. These cells also produce, in small amounts, an as yet undefined rat serum protein.

Cell Survival↗
PubMed1979

[Calcium and the permissive effect of glucocorticoids: the role of glucocorticoids in an adrenaline-induced increase in the rate of calcium absorption by the ventricular tissue of the rat heart].

It was demonstrated in rat experiments that the ability of the myocardial ventricles to increase 45Ca absorption after the injection of adrenaline was disturbed on the 3rd--5th day following adrenalectomy. The decrease in sensitivity to adrenaline occurred in two phases and was delayed essentially after a fall in the concentration of glucocorticoids in circulation. Chronic in vivo injection of hydrocortisone (2.5 mg per rat) into these animals for 3--5 days restored the effect of catecholamine to a great extent. The restorative effect was weaker when the rats were given a single intravenous hydrocortisone infusion 6 hours before being killed. Increase of the single intravenous dose of the hormone to 5 and 7.5 mg per rat reduced its effect. The authors assume that the described permissive effect of glucocorticoids is determined not by their direct interaction with the cytoplasmic membrane but by hormone induced intracellular synthesis of proteins capable of participating in the regulation of permeability to ions.

Absorption↗
PubMed1975

Glucocorticoid receptors in lung. Mechanism of specific glucocorticoid uptake by fetal rabbit lung nuclei.

After exposure of fetal rabbit lungs to glucocorticoid in vivo or in vitro, the hormone binds to specific receptors localized in the cytoplasm and in the nuclei. The present studies are compatible with a mechanism by which the nuclear receptor originates from the cytoplasm and arises from a hormone-, temperature-, and ionic strength-dependent transfer of the cytoplasmic receptor into the nucleus. This conclusion is reached from the following observations. Specific binding of glucocorticoid to nuclei from lungs not previously exposed to the hormone is not observed unless the cytosol is also present. In the presence of cytosol, nuclear uptake of the hormone is very slow at 0 degrees but is highly enhanced with increasing temperature. Concomitantly with the increased nuclear uptake there is an equiivalent loss of glucocortoid-receptor complex from the cytosol, indicating that the complex is transferred to the nuclei by a temperature-dependent process. Although the nuclei do not bind the cytoplasmic complex at 0 degrees, they do so provided that the cytosol is briefly heated in the presence of hormone prior to mixing with the nuclei. Thus the cytoplasmic complex must first be activated before it can bind to nuclei..

Animals↗
PubMed2020

Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4.

Glucocorticoids are potent endogenous anti-inflammatory molecules, and their cognate receptor, glucocorticoid receptor (GR), is expressed in nearly all immune cells. Macrophages are heterogeneous immune cells having a central role in both tissue homeostasis and inflammation and also play a role in the pathogenesis of some inflammatory diseases. Paradoxically, glucocorticoids have only a limited efficacy in controlling the resolution of these macrophage-related diseases. Here, we report that the transcriptomes of monocyte-like THP-1 cells and macrophage-like THP-1 cells (THP1-MΦ) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-MΦ significantly altered the sensitivity of gene transcription to glucocorticoids. Among glucocorticoid-regulated genes, we identified the exopeptidase dipeptidyl peptidase-4 (DPP4) as a critical glucocorticoid-responsive gene in THP1-MΦ. We found that GR directly induces DPP4 gene expression by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter. Additionally, we show that glucocorticoid-induced DPP4 expression is blocked by the GR antagonist RU-486 and by GR siRNA transfection and that DPP4 enzyme activity is reduced by DPP4 inhibitors. Of note, glucocorticoids highly stimulated macrophage mobility; unexpectedly, DPP4 mediated the glucocorticoid-induced macrophage migration, and siRNA-mediated knockdowns of GR and DPP4 blocked dexamethasone-induced THP1-MΦ migration. Moreover, glucocorticoid-induced DPP4 activation was also observed in proinflammatory M1-polarized murine macrophages, as well as peritoneal macrophages, and was associated with increased macrophage migration. Our results indicate that glucocorticoids directly up-regulate DPP4 expression and thereby induce migration in macrophages, potentially explaining why glucocorticoid therapy is less effective in controlling macrophage-dominated inflammatory disorders.

Animals↗
PubMed1979

Glucocorticoid receptors.

Glucocorticoid receptors are found in most mammalian tissues and have been studied in detail in a number of tissue culture systems. With cells that have not been exposed to steroids, the receptors are found in the cytoplasmic fraction from which they can be isolated and studied. Methods for studying glucocorticoid receptors depend on their high-affinity specific binding of radioactive steroids. The reversible interaction is intracellular. It follows Michaelian kinetics, at least in cell-free cytosol, and involves a thermodynamically homogeneous population of about 10 000 sites per cell. The receptor is an asymmetric, slightly acidic protein of about 100 000 daltons. It is very labile, especially in the unbound form. Binding activity depends on the integrity of thiol groups and perhaps on phosphorylation of amino acid residues. Although indirect, the evidence is overwhelmingly convincing that this protein is the physiologic glucocorticoid receptor. The time-kinetics of binding and dissociation are consistent with the sequence of events in glucocorticoid action. Various steroid analogs display binding characteristics predictable from their glucocorticoid activity. Loss of the binding protein from certain cultured cell lines is accompanied by unresponsiveness to glucocorticoids. The extensive tissue distribution of receptors parallels the extensive role of glucocorticoids in regulation. Finally, there is a strong correlation between nuclear binding of receptors and nuclear effects of the steroid. The glucocorticoid receptor can be distinguished from other glucocorticoid-binding proteins, based on their steroid specificity and physicochemical properties. There is no clear-cut demonstration that the receptor differs from tissue to tissue, and it is in fact very similar in various species. Unlike in other systems, receptor concentration does not seem to be regulated by its ligand or by other hormones. However, certain cases of hypo- as well as hypersensitivity to glucocorticoids appear to result from changes at the receptor level. The data indicate that the receptor can exist in inactive and active forms. The former predominate in the absence of steroid or when an angatonist is bound. Glucocorticoid agonists bind the active form, allowing it to be "activated" and subsequently bound to the nucleus. All of the receptors in isolated cytosol do not appear to be available for immediate occupancy by an agonist and this may be due to the time required for conversion of the receptors from inactive to active forms. The correlations between receptor binding and the glucocorticoid response indicate that the receptor is a rate-limiting factor in the magnitude and kinetics of the response, and this finding has important implications regarding mechanisms.

Animals↗
PubMed1979

Involvement of glucocorticoids in the development of the secondary palate.

Genetic differences between various inbred strains of mice in the levels of glucocorticoid receptors embryonic in maxillary mesenchyme cells appear to be reflected in the magnitude of the responses to steroids in these cells. High levels of glucocorticoids cause significant growth inhibition in maxillary mesenchyme cells with subsequent alterations in the production of extracellular matrix components. The presence of higher levels of cytoplasmic glucocorticoid receptor proteins may be one factor which could predispose those strains such as A/J to a greater inhibition of craniofacial growth in vivo by glucocorticoids and therefore increase the frequency of cleft palate production. Furthermore, women with infertility treated with glucocorticoids to support pregnancy give birth to infants with a marked decrease in birth weight [98]. Pharmacologic doses of glucocorticoids can also cause a dramatic reduction in the growth of a number of fetal tissues in mice and humans. In fact, there is evidence that glucocorticoids may be a causative factor in the production of cleft palate in primates [52]. The nature of the molecular elements which determine the biochemical and physiologic responses to glucocorticoids in the palate still remains largely unknown. Although in the mouse there is some evidence to suggest that the major histocompatibility locus (H-2) might be involved, the level(s) at which this control is exerted is unknown. It is possible that this locus may regulate in some manner the level of glucocorticoid receptors and the response to glucocorticoids in the secondary palate. Moreover, there is evidence to suggest that other genes distinct from, but closely linked to the H-2 locus may be important in determining both the strain-dependent differences in susceptibility to glucocorticoid-induced cleft palate and the intracellular levels of cyclic AMP in the secondary palate. It is also apparent that glucocorticoids in conjunction with other hormones or growth factors such as epidermal growth factor and agents which regulate cyclic nucleotide metabolism are essential for the normal development of the secondary palate. Excesses or deficiencies in either the level of these growth regulators and/or in their receptors in specific fetal tissues at defined periods in development are likely to lead to certain fetal malformations. Definition and integration of the genetic, biochemical, and endocrine factors which are involved in the control of cellular growth as influenced by alterations in the composition of cell surface and extracellular matrix components should provide some insights into the events associated with normal palatogenesis.

Animals↗
PubMed2025

The skeletal muscle of aged male mice exhibits sustained growth regulatory transcriptional profile following glucocorticoid exposure compared with young males.

Excess glucocorticoids induce skeletal muscle myopathy by changing gene expression. Advanced age augments glucocorticoid-mediated muscle phenotypes, yet the transcriptional responses underlying those augmented phenotypes are unclear. The purpose of this study was to define the glucocorticoid-responsive transcriptome in young and aged muscle following both acute and more prolonged glucocorticoid treatment. Young (4-mo-old) or aged (24-mo-old) male mice were administered either an acute injection of dexamethasone (DEX) or vehicle or daily DEX or vehicle injections for 7 days. Muscles were harvested 6.5 h after the final or only injection. The tibialis anterior (TA) was selected for RNA sequencing analysis as DEX treatment lowered TA mass specifically in aged males. In silico analyses identified enriched pathways and transcription factors predicted to regulate DEX-sensitive genes. Acute DEX altered similar numbers of genes in young (950) versus aged males (913), although aged males had greater magnitudes of fold change. After 7 days of DEX treatment, aged muscle exhibited more DEGs compared with acute exposure (1,196 vs. 913), whereas young muscle exhibited fewer DEGs than after acute exposure (599 vs. 950). In aged males, glucocorticoid-sensitive genes were consistently enriched for growth regulatory processes across both time points, a pattern that was not evident in young males. Despite those age-associated transcriptional differences, the transcription factors predicted to regulate the glucocorticoid-sensitive genes were similar in young and aged males. These data expand our understanding into how aging modifies the transcriptional response to excess glucocorticoids in skeletal muscle.NEW & NOTEWORTHY Glucocorticoids promote mass loss in certain muscles with advanced age but not at younger ages. In a muscle whose mass is lost in response to elevated glucocorticoids only in advanced age in males, we show that glucocorticoids initiate a unique and exaggerated transcriptional profile after both acute exposure to the hormone and after prolonged treatment that is consistent with muscle atrophy. These findings expand our understanding of the effect primary aging has on glucocorticoid-induced atrophy in males.

Animals↗
PubMed1975

Glucocorticoid-receptor interaction and induction of murine mammary tumor virus.

The relationship between the cellular uptake of glucocorticoid hormones, the binding of these hormones to specific in vitro receptors, and the induction of mouse mammary tumor viruses in an established mouse mammary tumor cell line was highly correlated. These results suggest that the induction of mouse mammary tumor virus by glucocorticoid hormones is a physiological process acting through a mechanism of high affinity, saturable steroid-receptors. A temperature-sensitive or salt-dependent step following glucocorticoid-receptor interaction was required for nuclear uptake of the steroid. Induction studies with different adrenocorticoids indicate that the synthetic glucocorticoid, dexamethasone (1,4-pregnadiene-9-fluor-16alpha-methyl-11beta,17alpha,21-triol-3,20-dione), is the most potent inducer of mouse mammary tumor viruses and all steroids which caused significant induction were glucocorticoids. Other glucocorticoids appear to stimulate murine mammary tumor virus production by a mechanism similar to that of dexamethasone; for example, corticosterone competes with dexamethasone for binding to the glucocorticoid receptor and blocks the uptake of dexamethasone into cells. Progesterone also blocks the cellular uptake of dexamethasone and can bind to the glucocorticoid receptor at low concentrations (10-7 to 10-8 M) but progesterone does not consistently induce virus at hormone concentrations even as high as 10-4 M. Thus, in this system, binding to a cytoplasmic receptor is necessary but not sufficient for induction by glucocorticoids. Estrogens and androgens interfere with receptor binding and cellular uptake of dexamethasone but only at much higher concentration (10-4 M) than progesterone, and do not induce mammary tumor virus production. Although there was a positive correlation between steroid structure, binding, and biologic induction, other factors clearly affect the physiological manifestations of steroid actions. Mouse cells with comparable cytoplasmic receptor levels and comparable nuclear uptake differed absolutely in their degree of murine mammary tumor virus induction following hormone treatment. Although all mouse cells examined contain comparable levels of murine mammary tumor virus DNA, only cells producing constitutive levels of murine mammary tumor virus RNA could be induced to higher levels by a variety of glucocorticoids.

Aldosterone↗
PubMed1979

Posttranscriptional regulation of glucocorticoid-regulated functions.

Relying heavily on studies of TAT regulation in cultured rat hepatoma cell lines, we have attempted in this brief review to discuss possible mechanisms for posttranscriptional regulation of glucocorticoid-sensitive enzymes and to chronicle the evidence for and against posttranscriptional mechanisms for specific enzyme induction by glucocorticoids. Initially, mechanisms were considered that would reconcile results showing sensitivity of both induction and deinduction of TAT to inhibitors of RNA synthesis with studies demonstrating first that glucocorticoids regulate the rates of specific enzyme synthesis and, then, that glucocorticoids regulate levels of enzyme-specific mRNA. Such reconciliation proved unnecessary when it was demonstrated that inhibitors of RNA synthesis such as actinomycin D were not specific for RNA synthesis, but also had effects on mRNA turnover and protein metabolism. The bulk of evidence to date establishes that glucocorticoids promote the production of enzyme-specific mRNA for the proteins whose synthesis is regulated by thses steroids. Nevertheless, there is still very little direct evidence that steroids can modulate rates of specific gene transcription. The glucocorticoid stimulation of mouse mammary tumor virus RNA production in cultured cell lines is the only example to date where such a mechanism is supported by RNA-DNA hybridization studies. Posttranscriptional actions of steroids on the turnover, processing, or extranuclear transport of specific mRNA precursors remain potential steps at which glucocorticoids might function. The rapid turnover of some glucocorticoid-regulated enzymes and their mRNAs not only ensures a rapid response to steroid addition or withdrawal, but also subjects these proteins to relatively large fluctuations upon alterations in overall protein or mRNA metabolism. Thus many of the inductions and repressions of hepatic TAT and TO by mediators other than the glucocorticoids may be attributable entirely to nonspecific mechanisms.

Animals↗